The invention disclosed herein is directed to certain spiro-substituted azacycles useful as tachykinin receptor antagonists. In particular, the compounds disclosed herein are neurokinin-3 receptor antagonists.
The tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), are structurally similar members of a family of neuropeptides. Each of these is an agonist of the receptor types, neurokinin-1 receptor (NK-1), neuorokinin-2 receptor (NK-2) and neuorokinin-3 receptor (NK-3), which are so defined according to their unique amino acid sequence and their relative abilities to bind tachykinins with high affinity and to be activated by the natural agonists SP, NKA and NKB respectively.
The tachykinins are distinguished by a conserved carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH.sub.2. More specifically, substance P is a pharmacologically-active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence:
SEQ ID NO:1: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH.sub.2 PA0 Neurokinin A possesses the following amino acid sequence: PA0 SEQ ID NO:2: His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH.sub.2. PA0 Neurokmin B possesses the following amino acid sequence: PA0 SEQ ID NO:3: Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH.sub.2. PA0 (Chang et al., Nature New Biol. 232, 86 (1971 ); D. F. Veber et al., U.S. Pat. No. 4,680,283).
The neurokinin receptors are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pernow, Pharmacol. Rev., 1983, 35, 85-141). The NK1 and NK2 receptor subtypes are implicated in synaptic transmission (Laneuville et al., Life Sci., 42:1295-1305 (1988)).
Substance P acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (see R. C. A. Frederickson et al., Science, 199, 1359 (1978); P. Oehme et al., Science, 208, 305 (1980)) and plays a role in sensory transmission and pain perception (T. M. Jessell, Advan. Biochem. Psychopharmacol. 28, 189 (1981 )). In particular, substance P has been shown to be involved in the transmission of pain in migraine (see B. E. B. Sandberg et al., Journal of Medicinal Chemistry, 25, 1009 (1982)), and in arthritis (Levine et al. Science, (1984) 226 547-549).
In the airways, it has been indicated that NK1 receptors are associated with microvascular leakage and mucus secretion, while NK2 receptors regulate smooth muscle contraction. Also, it has been shown that both substance P and neurokinin A are effective in inducing airway constriction and edema. Based on such findings, it is believed that substance P and neurokinin A may be involved in the pathogenesis of neurogenic inflammation, including allergic diseases such as asthma. (Frossard et al., Life Sci., 49, 1941-1953 (1991); Advenier, et al., Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992)).
In experimental studies, sensory neuropeptides, especially tachykinins such as substance P and neurokinin A, can bring about many of the pathophysiological features of asthma. Neurokinin A is a very potent constrictor of human airways in vitro, and substance P causes mucus secretion in the airways. (Barnes P. J., Lancet, pp242-44 (1986); Rogers D. R., Aursudkij B., Barnes P. J., Euro. J. Pharmacol, 174, 283-86 (1989)).
Inhalation of bradykinin causes bronchoconstriction in asthmatic patients but not in normal subjects. (Fuller R. W., Dixon C. M. S., Cuss F. M. C., Barnes P. J., Am Rev Respir Dis, 135, 176-80 (1987)). Since the bradykinin-induced bronchoconstriction is partly opposed by anticholinergic agents and since bradykinin is only a weak constrictor of human airways in vitro, it has been suggested that the bronchoconstrictor response is partly mediated by a neural reflex. Bradykinin stimulates vagal afferent C fibers and causes bronchoconstriction in dogs. (Kaufman M. P., Coleridge H. M., Coleridge J. C. G., Baker D. G., J. Appl. Physio., 48, 511-17 (1980)). In guinea-pig airways, bradykinin causes a bronchoconstrictor response by way of cholinergic and sensory-nerve-mediated mechanisms. (Ichinoe M., Belvisi M. G., Barnes P. J., J. Pharmacol. Exp. Ther., 253, 594-99 (1990). Bradykinin-induced bronchoconstriction in human airways may therefore be due partly to tachykinin released from sensory nerve terminals via axon reflex mechanisms. Clinical trials have shown that a dual NK-1/NK-2 antagonist (such as FK-224) protects against bradykinin induced bronchocontriction in asthmatic patients. (Ichinoe, M. et al., Lancet,, vol. 340, pp 1248-1251 (1992)).
The tachykinins have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract, such as inflammatory bowel disease, ulcerative colitis and Crohn's disease, etc. (see Mantyh et al., Neuroscience, 25 (3), 817-37 (1988) and D. Regoli in "Trends in Cluster Headache" Ed. F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, pp. 85-95).
It is also hypothesized that there is a neurogenic mechanism for arthritis in which substance P may play a role (Kidd et al., "A Neurogenic Mechanism for Symmetric Arthritis" in The Lancet, 11 November 1989 and Gronblad et al., "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. (1988) 15(12) 1807-10). Therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis (O'Byrne et al., in Arthritis and Rheumatism (1990) 33 1023-8). Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions (Hamelet et al., Can. J. Pharmacol. Physiol. (1988) 66 1361-7), immunoregulation (Lotz et al., Science (1988) 241 1218-21, Kimball et al., J. Immunol. (1988) 141 (10) 3564-9 and A. Perianin, et al., Biochem. Biophys. Res. Commun. 161,520 (1989)) vasodilation, bronchospasm, reflex or neuronal control of the viscera (Mantyh et al., PNAS (1988) 85 3235-9) and, possibly by arresting or slowing .beta.-amyloid-mediated neurodegenerative changes (Yankner et al., Science, (1990) 250, 279-82) in senile dementia of the Alzheimer type, Alzheimer's disease and Downs Syndrome. Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et. al., poster presented at C.I.N.P. XVIIIth Congress, 28th June-2nd July, 1992]. Antagonists selective for the substance P and/or the neurokinin A receptor may be useful in the treatment of asthmatic disease (Frossard et al., Life Sci., 49, 1941-1953 (1991); Advenier, et al., Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992)). These antagonists may also be useful in the treatment of emesis. See C. Bountra, K. Bounce, T. Dale, C. Gardner, C. Jordan. D. Twissell and P. Ward, Eur. J. Pharmacol., 249. R3-R4 (1993) "Anti-emetic profile of a non-peptide neurokinin NK1 receptor antagonist, CP-99,994, in the ferret.
The localisation of tachykinins and neurokinin receptor subtypes within the striatum is also heterogeneous. NKB immunoreactive fibres are colocalised within GABA containing neurones that project to the palladium but not the substantia nigra pars reticulata, whereas the SP containing neurones project principally to the substantia nigra pars reticulata. See Burgunder, J. M., & Young, W. S. 1989. Distribution, projection, and dopaminergic regulation of the neurokinin B mRNA-containing neurones of the rat caudate-putamen. Neurosci. 32, 323-335. Activation of tachykinin receptors in the straitum modulates the release of neurotransmitters including acetylcholine and dopamine See Tremblay, L., Kemel, M-L. Desban, M., Gauchy, C., & Glowinski, J. 1992. Distinct presynaptic control of dopamine release in stirosomal-matrix-enriched areas of the rat striatum by selective agonists of NK1, NK2 and NK3 tachykinin receptors. Proc. Natl. Acad. Sci. U.S.A. 89, 11214-11218. Interestingly in that study the release of dopamine by [Pro.sup.7 ]NKB (NK3) in the matrix compartment was insensitive to tetrodotoxin suggesting a presynaptic localisation of NK.sub.3 receptors.
This hypothesis is further supported by the finding that the NKB-induced stimulation of acetylchlorine release in rat striatum is reduced by both TTX and by lesions of the nigrostriatal pathway, and is consistent with the presence of NK.sub.3 receptors on dopamine cell bodies of the striatonigral and mesolimbic pathways. See Arenas, E., Alberch, J., Perez-Navarro, E., Solsona, C., Marsal, J. 1991. Neurokinin receptors differentially mediate endogenous acetylcholine release evoked by tachykinins in the neostriatum. J. Neurosci. 11 (8), 2332-2338; and Keegan, K. D., Woodruff, G., & Pinnock, R. D. 1992. The selective NK3 receptor agonist senktide excites a subpopulation of dopamine-sensitive neurones inthe rat substantia nigra pars compact in vitro. Br. J. Pharmacol. 105, 3-5.
We have found that Tachykinin receptor subtype on presumed dopamine neurones of the rat ventral tegmental area are a NK3 and not a NK1 or NK2 receptor subtype. These data suggest that NK3 receptors mediate the principal excitatory influence of tachykinins on mesolimbic dopamine neurones; however the role of receptors on afferent projections to the VTA and the relative tone of neuropeptide-containing fibres may have a more significant influence over their function.
Binding studies have shown NK.sub.3 -receptors to be present in brain slices from several species eg rat, mouse and guinea-pig, however, Dietl & Palacios, using .sup.125 I-labelled Bolton Hunter (BH) eledoisin reported an absence of NK3-receptors in primate and human brain. The human NK3-receptor was cloned from human brain mRNA, indicating that the protein is expressed in this tissue. See Huang, et al, BBRC 184:996-972 (1992). However, the cloned human NK3-receptor has lower affinity for eledoisin thatn the rat receptor and this probably explains the apparent absence of NK3-binding sites in human brain when 125I-BHeledoisin is used as the ligand. Indeed, using 3H-senktide Guard & Watson readily demonstrated the presence of NK3-binding sites in primate brain. See Dietl, M. M. & Palacios, J. M. Phylogeny and tachykinin receptor localisation in the vertebrate central nervous system: apparent absence of neurokinin-2 and neurokinin-3 binding sites in the human brain. 1991 Br Res 539:211-222; Buell, G., Schultz, S. J., Arkinstal, S. J., Maury, K., Missotten, M., Adami, N., Talabot, F. & Kawashin, E. Molecular characterisation, expression and localisation of human neurokinin-3 receptor. 1992 Febs Letts 299, 90-95; and Guard, S. & Watson, S. P. 1991 Neurochem Int 18:149-165.
Interestingly, infusion of senktide (an NK3-receptor agonist) by microdialysis in the substantia nigra and VTA of the rat caused behavioural responses characteristic of the activation of dopaminergic pathways and this effect was different with age. This observation implies that neurokinin receptors may play a role in central dopaminergic disorders, particularly those such as Parkinsonism which are more prelevant in advanced age. See Stoessl, A. J., Polanski, E. & Frydryszak, H. Effects of ageing on tachykinin function in the basal ganglia. 1993 Brain Res 632: 21-28.